Cholecystokinin (CCK) is a gastrointestinal hormone which is produced by and released from duodenal and jejunal mucous membranes, and is known to have actions such as secretion of pancreatic juice, gallbladder constriction, and stimulation of insulin secretion. CCK is also known to be present at high concentration in the cerebral cortex, hypothalamus, and hippocampus. CCK is also known to exhibit various actions, including inhibition of eating and hunger, augmentation of memory, and generation of anxiety. Meanwhile, gastrin is a gastrointestinal hormone which is produced by and released from G-cells distributed in the pylorus. Gastrin is also known to exhibit actions such as secretion of gastric acid and constriction of the pylorus and gallbladder. CCK and gastrin, having the same five amino acids in their C-terminals, exert the aforementioned actions via receptors. The receptors of CCK are classified into CCK-A receptors, which are of the peripheral-type and are distributed in the pancreas, the gallbladder, and the intestines; and CCK-B receptors, which are of the central-type and are distributed within the brain. Since gastrin receptors and CCK-B receptors show similar properties in receptor-binding experiments, and thus are proven to have high homology, they are often called CCK-B/gastrin receptors. Compounds having antagonism to these receptors, i.e., gastrin or CCK-B receptor, are expected to be useful for prevention and treatment of the following diseases and disorders: gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia, inflammation of the gallbladder, attack of biliary colic, motor disorders of alimentary canal, irritable bowel syndrome, certain types of tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson's disease, tardive dyskinesia, Gilles de la Tourette syndrome, drug dependence, and drug-withdrawal symptoms. Moreover, the compounds are expected to induce pain relief or to augment the pain-relieving effect of opioid analgesics (Folia Pharmacologica Japonica, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18. 919-931 (1993), American Journal of Physiology, Vol. 269, G628-G646 (1995), American Journal of Physiology, Vol. 259, G184-G190 (1990), European Journal of Pharmacology, 261, 257-263 (1994), Trends in Pharmacological Science, Vol. 15, 65-66 (1994)).
Proglumide, which is a drug having gastrin receptor antagonism, has conventionally been known as a remedy for gastric ulcer and gastritis. However, proglumide has a very weak affinity with gastrin or CCK-B receptors, and has a low curative effect. It is described that some 1,4-benzodiazepine derivatives--such as L-364,718 (Dibazepaido, Japanese Patent Application Laid-Open (kokai) No. 63666/1986) and L-365,260 (Japanese Patent Application Laid-Open (kokai) No. 238069/1988)--exhibit CCK-A receptor antagonism or CCK-B receptor antagonism. It is also known that compounds having strong CCK-B receptor antagonism suppress secretion of gastric acid stimulated by pentagastrin (WO 94/438 and WO 95/18110). However, these compounds do not provide satisfactory effects when administered in vivo. Drugs which exhibit gastrin or CCK-B receptor antagonism and are clinically useful have not yet been provided.
Compounds that can be strongly bound to gastrin or cholecystokinin receptors are expected to be useful as remedies and for prevention of diseases associated with respective receptors and found in the alimentary canal and the central nervous system.